The present invention relates to an improved process for producing directly tabletable ibuprofen formulations by mixing ibuprofen with a finely divided excipient, and to the formulations obtained correspondingly.
Direct tableting is a process frequently used in the production of tablets because it is simpler and more cost-efficient. Direct tableting is therefore becoming increasingly important.
Up to 800 mg of ibuprofen is administered per tablet. Since it is wished to ensure that there are no swallowing problems, the ibuprofen content in ibuprofen tablets is normally very high. This high ibuprofen content in an ibuprofen formulation leads to the properties for example of the tableting mixture being determined almost exclusively by the properties of ibuprofen. The low melting point of ibuprofen of only 75° C. therefore causes serious difficulties in the processing of a formulation, such as, inter alia, adhesion to the compression tools and low tableting speeds. Besides the tendency to adhere, the high ibuprofen content also frequently leads to poor flowability because the ibuprofen crystals are usually in a form with a size in the region of 50 μm.
The unwanted phenomenon of adhesion to the compression tools increases as the duration of a production cycle increases. On the other hand, a manufacturer will always attempt, for cost reasons, to have a production cycle running for as many hours as possible without, for example, polishing or dismantling punch tools.
Problems arise in the processing of ibuprofen-containing mixtures especially with relatively low compressive forces too. On the other hand, a pharmaceutical manufacturer will always attempt to operate with compressive forces which are as low as possible in order to save the high-cost compression tools from wear.
In general, problems arise during processing of ibuprofen owing to its tendency to adhere because of the relatively low melting point. Even during the mixing process to produce dry ibuprofen-containing mixtures there may be sticking of the mixing tools especially with a high energy input and heating of the agitators.
U.S. Pat. No. 5,191,114 discloses a process for producing ibuprofen powders for direct tableting, in which powders with improved flowability are said to be obtained by dry mixing of ibuprofen with amorphous silica gel. As is known to the skilled worker, the flowability can be improved in this way after only a short mixing time. However, the tabletability is not improved in practice in this way.
EP-A 172 014 likewise describes the production of ibuprofen-containing formulations, where the ibuprofen is mixed with sodium croscarmellose as disintegrant and small amounts of colloidal silica with short mixing times in the region of a few minutes, and is subsequently roll-compacted. An insufficient improvement in tabletability is achieved with these formulations too.
WO 2005/037192 likewise describes the production of ibuprofen-containing granules by dry mixing of the active ingredient with pharmaceutical aids and subsequent roll compaction.